Bigeminy compound medicine composition for treating glaucoma and application of bigeminy compound medicine composition

Abstract

The invention provides a bigeminal compound medicine composition and application thereof, and belongs to the field of medicines. The pharmaceutical composition comprises carteolol or timolol, netasdil, a buffering agent, a tension agent, a pH regulator, a tackifier and water for injection. According to the invention, the problem that netardil and carteolol or timolol are insoluble is successfully solved by adding the pH regulator into the solution of netardil free alkali and carteolol free alkali or timolol free alkali. The preparation process is simple, intraocular pressure is reduced through different action mechanisms, and the curative effect is obvious and exact. The ophthalmic pharmaceutical composition provides possibility for safely and effectively reducing intraocular pressure and treating glaucoma clinically.

Description

Technical Field

[0001] The invention belongs to the field of medicines, and in particular relates to a dual compound pharmaceutical composition and uses thereof. Background Art

[0002] Glaucoma is a group of multifactorial optic nerve diseases, accompanied by characteristic optic nerve damage and corresponding visual field defects. Severe glaucoma patients may even go blind. Therefore, glaucoma has become the number one killer of blindness in humans.

[0003] Increased intraocular pressure is one of its primary risk factors. According to statistics, the number of glaucoma patients in the world in 2020 is about 7.6-79.6 million, and the global prevalence of glaucoma in people aged 40-80 is about 3.54%. There are many types of glaucoma, such as primary glaucoma, secondary glaucoma and congenital glaucoma, many of which are closely related to age. Therefore, against the backdrop of an aging global population, the number of glaucoma patients is also increasing, and by 2040, the number of glaucoma patients may exceed 111.8 million.

[0004] So far, the only globally recognized method to control the development of glaucoma is to lower intraocular pressure. As the earliest method used to treat glaucoma, drugs have always played a very important role in the treatment of glaucoma.

[0005] At present, the commonly used single-ingredient preparations are as follows: (1) Rho kinase inhibitors: IOP-lowering drugs that act directly on the trabecular meshwork, mainly by affecting the cytoskeleton to change the morphology of trabecular meshwork cells, cell movement, cytoplasmic division and smooth muscle contraction, thereby increasing aqueous humor outflow, protecting the optic nerve, and reducing bleb scarring. The commonly used drug in clinical practice is natriuretic peptide dimethanesulfonate. (2) Adrenergic β-receptor blockers: They can reduce the production of aqueous humor and promote the drainage of aqueous humor by blocking β-receptors. They have a strong and sustained IOP-lowering effect and effectively control IOP. The commonly used drugs in clinical practice are timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, levobunolol hydrochloride, etc.; (3) α 2 Adrenergic receptor agonists: They reduce intraocular pressure by reducing the production of aqueous humor and outflow through the sclera, and are the first-line drugs for the treatment of primary open-angle glaucoma. The drug commonly used in clinical practice is brimonidine tartrate; (4) Prostaglandin analogs: They reduce intraocular pressure by relaxing the ciliary muscle, increasing the intermuscular space, and increasing the outflow and drainage of aqueous humor through the uveosclera. They have a strong effect in reducing intraocular pressure at night, especially for patients who cannot tolerate or have poor effects on other ocular hypotensive drugs. The drugs commonly used in clinical practice are latanoprost, bimatoprost, travoprost, tafluprost, etc.

[0006] Glaucoma is a chronic eye disease that requires long-term medication. However, single-drug preparations often cannot effectively control intraocular pressure and require the use of two drugs in combination. As the frequency of drug administration increases, the exposure to preservatives will also increase significantly, leading to problems such as poor safety, more side effects, and poor patient compliance.

[0007] Thickeners can prolong the residence time of drugs on the ocular surface through physical thickening, membrane affinity and drug binding, so that drugs are confined to the eye and are not easy to flow into the mouth and nasal cavity, reducing the absorption of drugs by the mouth and nasal cavity, thereby improving the bioavailability of drugs in the eye. Most of the eye drops containing thickeners on the market are artificial tears, which are used to treat dry eyes, such as sodium hyaluronate eye drops, sodium carboxymethyl cellulose eye drops, polyvinyl alcohol eye drops and polyethylene glycol eye drops. Other eye drops with thickeners, such as Mikelan for the treatment of glaucoma, are also available. Sodium alginate is also added as a thickener to increase its viscosity; although eye drops with a certain viscosity can increase the residence time of the drug on the ocular surface, improve comfort, and reduce the frequency of use, they can also easily cause blurred vision and bring inconvenience to patients' lives.

[0008] In addition, since the salt forms of natadil dimesylate and carteolol hydrochloride are insoluble in each other, the development of compound eye drops is limited. Therefore, it is a technical problem to be solved urgently by those skilled in the art to develop a dual compound pharmaceutical composition for treating eye diseases with a simple preparation process, excellent stability, high safety, and good patient compliance. Summary of the invention

[0009] In order to overcome the deficiencies of the prior art, the purpose of the present invention is to provide a dual compound pharmaceutical composition and its use, which is a dual compound pharmaceutical composition solution for ophthalmology containing natadil free base and carteolol free base, which has a simple preparation process, excellent stability, high safety and good patient compliance. It can be used to treat glaucoma, high intraocular pressure and / or symptoms related thereto, and a once-daily dose can effectively and quickly reduce intraocular pressure, has few side effects and high patient compliance.

[0010] To solve the above problems, the technical solution adopted by the present invention is as follows: a dual compound pharmaceutical composition, the pharmaceutical composition comprising: carteolol or timolol, natridil, a buffer, a tonicity agent, a pH regulator, a viscosity enhancer, and water for injection.

[0011] Among them, 5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3,4-dihydro-2(1H)-quinolone (Carteolol), 4-[(1S)-1-(aminomethyl)-2-(6-isoquinolyl)-2-oxoethyl]phenyl]methyl 2,4-dimethylbenzoate (Natamidil)

[0012] The preferred ophthalmic pharmaceutical composition comprises:

[0013] (1) 0.02% w / v to 4.0% w / v of the adrenergic beta-receptor blocker carteolol free base or timolol free base;

[0014] (2) 0.005% w / v to 0.1% w / v of natriuretic acid free base;

[0015] (3) 0.01% w / v to 10.0% w / v tonicity agent;

[0016] (4) 0.01% w / v to 1.0% w / v buffer;

[0017] (5) 0.1% w / v to 1.0% w / v of a viscosity increasing agent;

[0018] (6) adjusting the pH to 4.5 to 5.4 using a pH adjuster;

[0019] (7) Osmolality is 280 to 320 mOsmol / kg.

[0020] Furthermore, the ophthalmic pharmaceutical composition comprises

[0021] (1) 0.02% w / v to 2.0% w / v of carteolol free base or timolol free base;

[0022] (2) 0.005% w / v to 0.02% w / v of natadil free base;

[0023] (3) 0.01% w / v to 10.0% w / v tonicity agent;

[0024] (4) 0.01% w / v to 1.0% w / v buffer;

[0025] (5) 0.1% w / v to 1.0% w / v of a viscosity increasing agent; v is the volume of the composition system after the injection water is added;

[0026] (6) adjusting the pH to 4.5 to 5.4 using a pH adjuster;

[0027] (7) Osmolality is 280 to 320 mOsmol / kg.

[0028] Preferably, in the composition solution, the tonicity agent includes but is not limited to glycerol, sorbitol, mannitol, propylene glycol, erythritol, arabitol, xylitol, ribitol, galactitol, polyethylene glycol, lactitol, mannitol, dextrose and other sugar alcohols, sodium chloride, potassium chloride, and calcium chloride, or any combination thereof.

[0029] Preferably, the composition solution, wherein the buffer includes but is not limited to boric acid or its salts, sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate monohydrate, sodium phosphate anhydrate, citric acid or its salts, carbonic acid, gluconic acid or its salts, acetic acid or its salts, phosphoric acid or its salts, various amino acids such as glutamic acid and ε-aminocaproic acid and trimethylolmethane buffer, or any combination thereof.

[0030] Preferably, in the composition solution, the viscosity increasing agent includes but is not limited to one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium hydroxyethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, polyethylene glycol, sodium hyaluronate, sodium alginate, chitosan, and polyvinyl pyrrolidone.

[0031] Preferably, in the composition solution, examples of pH adjusters include but are not limited to methanesulfonic acid, hydrobromic acid, phosphoric acid, hydrochloric acid, citric acid, tartaric acid, malic acid, lactic acid, succinic acid, hydroiodic acid, formic acid, acetic acid, benzoic acid, ethanesulfonic acid, oxalic acid, sodium hydroxide, and tromethamine.

[0032] Preferably, the composition solution comprises 0.02% w / v to 4.0% w / v of the adrenergic beta receptor blocker carteolol free base; more preferably 0.3% w / v to 2.0% w / v, and most preferably 2.0% w / v. 0.02% w / v to 4.0% w / v of the adrenergic beta receptor blocker timolol free base; more preferably 0.1% w / v to 2.0% w / v, and most preferably 0.5% w / v.

[0033] Preferably, the composition solution comprises 0.005% w / v to 0.1% w / v of natadil free base; more preferably 0.02% w / v to 0.04% w / v, most preferably 0.02% w / v.

[0034] Preferably, the composition solution comprises 1.0% w / v to 10.0% w / v mannitol.

[0035] Preferably, the composition solution comprises 0.05% w / v boric acid.

[0036] Preferably, the composition solution comprises 0.5%-1.0% w / v of hypromellose; more preferably 0.5% w / v of hypromellose.

[0037] Preferably, the composition solution has an osmotic pressure of 280-320 mOsmol / kg.

[0038] Preferably, the pH of the composition solution is 4.5-5.4.

[0039] Preferably, the composition solution provided by the present invention is subjected to a stability test. The results show that when stored at 5°C ± 3°C for 24 months, the content of each main drug component has no significant change compared with day 0, which is consistent with the storage conditions of commercial eye drops before opening.

[0040] Preferably, the composition solution provided by the present invention is subjected to a stability test. The results show that when stored at 25°C ± 2°C for 6 weeks, the content of each main drug component has no significant change compared with day 0, which meets the requirements for storage conditions of commercially available eye drops after opening.

[0041] Preferably, the composition solution provided by the present invention is subjected to a stability test. The results show that when stored at 40°C ± 2°C for 14 days, the content of each main drug component has no significant change compared with day 0, which meets the requirements for short-term deviation of storage conditions for commercially available eye drops.

[0042] The present invention further provides the use of the dual compound pharmaceutical composition in the preparation of a drug for preventing or treating an eye disease. Preferably, the eye disease is glaucoma, high intraocular pressure and / or symptoms related thereto.

[0043] The compound eye drops for treating glaucoma, high intraocular pressure and / or symptoms related thereto comprise applying the aforementioned ophthalmic pharmaceutical composition solution to the eyes of a patient in need thereof once a day.

[0044] The beneficial effects of the technical solution of the present invention are: (1) Due to the incompatibility of the salt forms of natriuretic acid dimesylate and the adrenergic beta-receptor blocker carteolol hydrochloride, the development of compound eye drops prepared from the two drugs is limited; the present invention successfully solves the problem of the incompatibility of the two drugs by adding a pH regulator to the natriuretic acid free base and carteolol free base solutions. The preparation process is simple and provides a method for solving the incompatibility of the salt forms of the two drugs. This method is expected to provide a solution for the dissolution of other incompatible drugs; (2) It can reduce intraocular pressure through different mechanisms of action, and the therapeutic effect is obvious and definite; (3) The viscosity enhancer provides a longer retention time on the ocular surface. Compared with traditional prescription eye drops, the present invention can reduce the amount of ocular surface loss of eye drops, and is expected to allow more drugs to penetrate the cornea and provide a stronger effect of lowering intraocular pressure; compared with commercially available single-ingredient preparations ( Compared with eye drops, the ocular hypotensive effect is significantly enhanced by once-a-day administration; (4) once-a-day administration not only reduces the number of administrations, but also the preservative-free prescription can eliminate the exposure of preservatives, reduce the occurrence of ocular side effects, and significantly improve patient compliance. At the same time, the pharmaceutical composition solution provided by the present invention is useful as a therapeutic agent for glaucoma, high intraocular pressure and / or symptoms related thereto. Therefore, the ophthalmic pharmaceutical composition of the present invention provides the possibility of safely and effectively reducing intraocular pressure and treating glaucoma clinically. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 It is a diagram showing the dosing schedule of the ophthalmic pharmaceutical composition solution of Examples 1-30 of the present invention, the positive control drug treatment group 1, and the positive control drug treatment group 2.

[0046] FIG. 2 is a graph showing the measured intraocular pressure values ​​of the ophthalmic pharmaceutical composition solutions of Examples 1-30 of the present invention and the positive control drug after administration ( Figure 2-1 ) and the difference in intraocular pressure change ( Figure 2-2 ) Column Chart

[0047] Figure 3 It is a diagram showing the dosing schedule of the ophthalmic pharmaceutical composition solution of Examples 31-60 of the present invention, the positive control drug treatment group 1, and the positive control drug treatment group 2.

[0048] FIG. 4 is a graph showing the measured intraocular pressure values ​​of the ophthalmic pharmaceutical composition solutions of Examples 31-60 of the present invention and the positive control drug after administration ( Figure 4-1 ) and intraocular pressure change value ( Figure 4-2 ) column chart.

[0049] Figure 5 It is a diagram showing the dosing schedule of the ophthalmic pharmaceutical composition solution of Examples 61-90 of the present invention, the positive control drug treatment group 1, and the positive control drug treatment group 2.

[0050] FIG. 6 is a graph showing the intraocular pressure changes of rabbits in the ophthalmic pharmaceutical composition solutions of Examples 61-90 of the present invention and the positive control drug groups ( Figure 6-1 ) and measured intraocular pressure ( Figure 6-2 ) column chart.

[0051] Figure 7 It is a diagram showing the dosing schedule of the ophthalmic pharmaceutical composition solution of Examples 91-120 of the present invention, the positive control drug treatment group 1, and the positive control drug treatment group 2.

[0052] FIG8 is a bar graph showing the intraocular pressure change values ​​of the ophthalmic pharmaceutical composition solutions of Examples 91-120 and the positive control drug when no viscosity enhancer is added to the present invention ( Figure 8-1 ) and the bar graph of measured intraocular pressure values ​​( Figure 8-2 ).

[0053] 9 is a graph showing the significant difference in intraocular pressure change values ​​of the ophthalmic pharmaceutical composition solution on day 20 between the group without viscosity increasing agent and the group with hydroxypropyl methylcellulose (HPMC).

[0054] FIG. 10 is a graph showing the significant difference in intraocular pressure change values ​​of the ophthalmic pharmaceutical composition solution on the 20th day between the group without viscosity enhancer and the group with polyethylene glycol (PEG), wherein Figure 10-1 represents an ophthalmic pharmaceutical composition solution containing 1% carteolol, Figure 10-2 Indicates an ophthalmic pharmaceutical composition solution containing 2% carteolol.

[0055] FIG. 11 is a graph showing the significant difference in intraocular pressure change values ​​of the ophthalmic pharmaceutical composition solution on the 20th day between the group without viscosity enhancer and the group with sodium hyaluronate (HA), wherein Figure 11-1 represents an ophthalmic pharmaceutical composition solution containing 1% carteolol, Figure 11-2 Indicates an ophthalmic pharmaceutical composition solution containing 2% carteolol.

[0056] Fig.12 It is a diagram showing the dosing schedule of the ophthalmic pharmaceutical composition solution of Examples 126-129 of the present invention, the positive control drug treatment group 1, and the positive control drug treatment group 3.

[0057] 13 is a diagram showing the ophthalmic pharmaceutical composition solution of Examples 126-129 of the present invention plus hydroxypropyl methylcellulose (HPMC) and the positive control drug ( Eye drops) were administered once a day starting from the 10th day for 10 consecutive days. The intraocular pressure changes of rabbits in each group were measured on the 20th day ( Figure 13-1 ) and measured intraocular pressure ( Figure 13-2 ) data.

[0058] FIG. 14 is a graph showing the significant difference in intraocular pressure change values ​​of the ophthalmic pharmaceutical composition solution on the 20th day between the group without viscosity enhancer and the group with hydroxypropyl methylcellulose (HPMC), wherein Figure 14-1 It means an ophthalmic pharmaceutical composition solution containing 0.25% timolol. Figure 14-2 It represents an ophthalmic pharmaceutical composition solution containing 0.5% timolol. DETAILED DESCRIPTION

[0059] The present invention is further described in detail below with reference to the embodiments, but is not limited thereto.

[0060] The present invention is a therapeutic agent for glaucoma, high intraocular pressure and / or symptoms related thereto, which is an ophthalmic dual compound pharmaceutical composition solution comprising adrenaline beta receptor blocker carteolol free base or timolol free base and natadil free base.

[0061] In the present invention, different pH regulators are added to directly salt the free base of natridil and the free base of carteolol or the free base of timolol, thereby successfully solving the problem of incompatibility between the mesylate of natridil and the salt type of carteolol hydrochloride or the timolol maleate.

[0062] In the ophthalmic pharmaceutical composition solution of the present invention, the concentration of the adrenergic beta receptor blocker carteolol free base is 0.02% w / v to 4.0% w / v, more preferably 0.3% w / v to 2.0% w / v, and most preferably 2.0% w / v; the concentration of timolol free base is 0.02% w / v to 4.0% w / v, more preferably 0.1% w / v to 2.0% w / v, and most preferably 0.5% w / v.

[0063] In the ophthalmic pharmaceutical composition solution of the present invention, the concentration of natadil free base is 0.005% w / v to 0.1% w / v, more preferably 0.02% w / v to 0.04% w / v, most preferably 0.02% w / v.

[0064] In the ophthalmic pharmaceutical composition solution of the present invention, a tonicity agent may be included. By using conventional materials known in the art, the tonicity or osmolality of the composition can be adjusted to hypotonicity, isotonicity or hypertonicity relative to normal tears. Tonicity agents are generally non-ionic compounds. Examples of tonicity agents include, but are not limited to, sodium chloride, potassium chloride, mannitol, dextrose, glycerol and propylene glycol. Suitably, the tonicity agent may be present in the ophthalmic composition in an amount of about 0.01% w / v to about 10% w / v. In an embodiment, the tonicity agent may be present in the ophthalmic composition in an amount of about 1.0% w / v, about 1.1% w / v, about 1.2% w / v, about 1.3% w / v, about 1.4% w / v, about 1.5% w / v, about 1.6% w / v, about 1.7% w / v, about 1.8% w / v, about 1.9% w / v, about 2.0% w / v, about 2.1% w / v, about 2.2% w / v, about 2.3% w / v, about 2.4% w / v, about 2.5% w / v, about 2.6% w / v, about 2.7% w / v, about 2.8% w / v, about 2.9% w / v, or about 3.0% w / v. The tonicity agent may suitably be mannitol.

[0065] In the ophthalmic pharmaceutical composition solution of the present invention, a buffer may be included. Buffers can be used to minimize pH drift of the composition and help stabilize the composition. Suitable buffers include, but are not limited to, acetic acid, citric acid, carbonic acid, phosphoric acid, boric acid, their pharmaceutically acceptable salts, tromethamine, and combinations thereof. The buffer may be present in the ophthalmic composition in an amount of about 0.01% w / v to about 1% w / v. In an embodiment, the buffer may be present in the ophthalmic composition in an amount of about 0.01% w / v, about 0.02% w / v, about 0.03% w / v, about 0.04% w / v, about 0.05% w / v, about 0.06% w / v, about 0.07% w / v, about 0.08% w / v, about 0.09% w / v, or about 0.1% w / v. The buffer may suitably be boric acid.

[0066] In the ophthalmic pharmaceutical composition solution of the present invention, a viscosity enhancer may be included. The viscosity enhancer can increase the retention time of the drug on the ocular surface to improve the therapeutic effect. Suitable viscosity enhancers include but are not limited to hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, sodium hyaluronate, hyaluronic acid, chitosan, etc. The viscosity enhancer may be present in the ophthalmic composition in an amount of about 0.1% w / v to 1.0% w / v. In an embodiment, the buffer may be present in the ophthalmic composition in an amount of about 0.3% w / v, about 0.4% w / v, about 0.5% w / v, about 0.6% w / v, about 0.7% w / v, about 0.8% w / v, or about 0.9% w / v. The viscosity enhancer may suitably be hydroxypropyl methylcellulose, polyethylene glycol, sodium hyaluronate.

[0067] In the ophthalmic pharmaceutical composition solution of the present invention, a pH adjuster may be contained in an amount sufficient to adjust the pH of the composition to about 4 to about 9. Suitably, the pH of the ophthalmic composition may be about 4.5 to about 5.4. Suitable pH adjusters include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium bicarbonate, methanesulfonic acid, hydrobromic acid, phosphoric acid, hydrochloric acid, citric acid, tartaric acid, malic acid, lactic acid, succinic acid, hydroiodic acid, formic acid, acetic acid, benzoic acid, ethanesulfonic acid, and oxalic acid.

[0068] Example 1-30: Dual compound eye drops prepared with hydroxypropyl methylcellulose as a viscosity enhancer and different pH adjusters

[0069] Table 1. Preparation and formulation of topical ophthalmic pharmaceutical composition solutions for reducing intraocular pressure are as follows:

[0070]

[0071] The preparation process is as follows: (1) Weigh 90% of the prescribed amount of water for injection, add the prescribed amount of carteolol, boric acid, mannitol, natridil and hydroxypropyl methylcellulose, add different pH adjusters, stir and adjust the pH to 4.5-5.4; (2) Add water for injection to the full amount of the prescription, stir evenly and make the volume reach 100%; (3) Put the solution of step 2 into a low-density polyethylene medicinal eye drop bottle, and study its stability under different storage temperature conditions. Table 2. Content of each main drug component in Examples 1-30 when stored at 5°C for 24 months

[0072]

[0073]

[0074] Table 3. Commercially available eye drops stored at 5°C for 24 months ( The content of each main drug component in eye drops

[0075]

[0076] According to Examples 1-30, the preparations containing natadil and carteolol have good stability under storage conditions of 5° C. for 24 months, meeting the requirements for commercially available eye drops ( Eye drops) Storage conditions requirements before opening.

[0077] Table 4. Content of each main drug component in Examples 1-30 when stored at 25°C for 6 weeks

[0078]

[0079]

[0080] Table 5. Commercially available eye drops stored at 25°C for 6 weeks ( The content of each main drug component in eye drops

[0081]

[0082] According to Examples 1-30, the preparations containing natridil and carteolol have good stability under storage conditions of 25° C. for 6 weeks, meeting the requirements for commercially available eye drops ( Eye drops) Storage conditions requirements after opening.

[0083] Table 6. Content of each main drug component in Examples 1-30 when stored at 40°C for 14 days

[0084]

[0085]

[0086] Table 7. Commercially available eye drops stored at 40°C for 14 days ( Eye drops) Content of each main drug component

[0087]

[0088] According to Examples 1-30, the preparations containing natridil and carteolol have good stability for 14 days under storage conditions of 40° C., meeting the requirements for commercially available eye drops ( Eye drops) short-term deviation from storage conditions requirements.

[0089] Example 31-60: Dual compound eye drops prepared with polyethylene glycol as a thickener and different pH adjusters

[0090] Table 8. Preparation and formulation of topical ophthalmic pharmaceutical composition solution for reducing intraocular pressure are as follows:

[0091]

[0092]

[0093] The preparation process is as follows: (1) weigh 90% of the prescribed amount of water for injection, add the prescribed amount of carteolol, boric acid, mannitol, natridil and polyethylene glycol, add different pH adjusters, stir and adjust the pH to 4.5-5.4; (2) add water for injection to the full amount of the prescription, stir evenly and make the volume reach 100%; (3) put the solution of step 2 into a low-density polyethylene medicinal eye drop bottle, and study its stability under different storage temperature conditions.

[0094] Examples 61-90: Dual compound eye drops prepared with sodium hyaluronate as the viscosity enhancer and different pH adjusters

[0095] Table 15. Preparation and formulation of topical ophthalmic pharmaceutical composition solution for reducing intraocular pressure are as follows:

[0096]

[0097]

[0098] The preparation process is as follows: (1) weigh 90% of the prescribed amount of water for injection, add the prescribed amount of carteolol, boric acid, mannitol, natridil and sodium hyaluronate, add different pH adjusters, stir and adjust the pH to 4.5-5.4; (2) add water for injection to the full amount of the prescription, stir evenly and make the volume reach 100%; (3) put the solution of step 2 into a low-density polyethylene medicinal eye drop bottle, and study its stability under different storage temperature conditions.

[0099] Examples 91-120: Thickener-free dual compound eye drops prepared with different pH adjusters

[0100] Table 22. Preparation and formulation of topical ophthalmic pharmaceutical composition solution for reducing intraocular pressure are as follows:

[0101]

[0102]

[0103] The preparation process is as follows: (1) weighing 90% of the prescribed amount of water for injection, adding the prescribed amount of carteolol, boric acid, mannitol, and natriuretic acid, adding different pH adjusters, stirring, and adjusting the pH to 4.5-5.4; (2) adding water for injection to the full amount of the prescription, stirring evenly and making the volume reach 100%; (3) putting the solution of step 2 into a low-density polyethylene medicinal eye drop bottle. After testing, the stability of the composition under different storage temperature conditions is good.

[0104] Example 121: Evaluation of the efficacy of the ophthalmic pharmaceutical composition solution of the present invention using the Japanese white rabbit glaucoma model

[0105] In this example, intracameral injection of compound carbomer (containing 0.3% by weight of main drug carbomer and 0.025% by weight of dexamethasone) was used to prepare a model of high intraocular pressure, and the eye drops prepared in Examples 1-30 were administered once a day to evaluate the therapeutic effect.

[0106] Experimental animals: 102 healthy male Japanese white rabbits, with an initial body weight of 2.5-3.0 kg.

[0107] Experimental groups:

[0108] Normal control group: no treatment.

[0109] Model group: The high intraocular pressure model was established without any eye drops.

[0110] Treatment group 1: The model of intraocular hypertension was established and the commercially available natadil eye drops ( Eye drops, a single-ingredient preparation containing 0.02 parts by weight of the main drug, natadil).

[0111] Treatment group 2: The model of intraocular hypertension was established and commercially available carteolol hydrochloride eye drops ( Eye drops, a single-ingredient preparation containing 2.0 parts by weight of the main drug carteolol).

[0112] Example 1 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is methanesulfonic acid.

[0113] Example 2 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is methanesulfonic acid.

[0114] Example 3 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity increasing agent is hypromellose and the pH adjusting agent is hydrobromic acid.

[0115] Example 4 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is hydrobromic acid.

[0116] Example 5 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is phosphoric acid.

[0117] Example 6 Group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is phosphoric acid.

[0118] Example 7 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity increasing agent is hypromellose and the pH adjusting agent is hydrochloric acid.

[0119] Example 8 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is hydrochloric acid.

[0120] Example 9 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is citric acid.

[0121] Example 10 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is citric acid.

[0122] Example 11 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is tartaric acid.

[0123] Example 12 Group: The viscosity enhancer is hypromellose and the pH adjuster is tartaric acid (a dual compound preparation containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0124] Example 13 Group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is malic acid.

[0125] Example 14 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is malic acid.

[0126] Example 15 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is lactic acid.

[0127] Example 16 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is lactic acid.

[0128] Example 17 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is succinic acid.

[0129] Example 18 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is succinic acid.

[0130] Example 19 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is hydroiodic acid.

[0131] Example 20 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is hydroiodic acid.

[0132] Example 21 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is formic acid.

[0133] Example 22 Group: An ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is formic acid.

[0134] Example 23 Group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is acetic acid.

[0135] Example 24 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is acetic acid.

[0136] Example 25 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is benzoic acid.

[0137] Example 26 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is benzoic acid.

[0138] Example 27 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is ethanesulfonic acid.

[0139] Example 28 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is ethanesulfonic acid.

[0140] Example 29 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is oxalic acid.

[0141] Example 30 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is oxalic acid.

[0142] Model establishment: The normal control group rabbits were not treated in any way. The other 33 groups of rabbits were injected with urethane 0.8-1g / kg through the ear vein on day 0. The rabbits were anesthetized and 10μl of aqueous humor was taken out of each anterior chamber of the eye using a 1ml syringe. Then 10μl of the two-compound carbomer solution was injected. The intraocular pressure was measured every two days and the clinical manifestations were observed. In the successful model, the anterior chamber became turbid and the intraocular pressure increased significantly. After 10 days, the rabbit model of high intraocular pressure was successfully established.

[0143] Dosage regimen: According to the currently available natadil eye drops ( eye drops) and commercially available carteolol hydrochloride eye drops ( The clinical dosing regimen of eye drops) was mainly divided into the following groups: (1) Treatment group 1: commercially available natadil eye drops ( Eye drops), 50 μL per eye, once a day (9:00 PM); (2) Treatment group 2: commercially available carteolol hydrochloride eye drops ( Eye drops), 50 μL per eye, twice a day (9:00 AM, 9:00 PM); (3) Example 1-30 group: 50 μL per eye, once a day (9:00 PM). All groups were successfully established on the 10th day and began to receive medication, which lasted for 10 days. The normal control group and the model group were not given eye drops. The medication regimen is as follows Figure 1 shown.

[0144] Detection indicators and methods:

[0145] Intraocular pressure: On the 0th, 2nd, 4th, 6th, 8th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, and 20th day of the experiment, intraocular pressure was tested once a day (9:00 PM). Gently pull open the upper and lower eyelids of the rabbit, bring the tonometer close to the rabbit's eyes, adjust the distance, and gently press the measurement button. Do not touch the eyelids during the measurement process. Complete 6 measurements in sequence to obtain the single measurement value and the average value (mmHg).

[0146] Experimental results:

[0147] Intraocular pressure: At all post-dose time points during the study, the IOP values ​​of all treatment groups and example groups were significantly lower than those of the model group (Student paired t-test). At the same time, compared with treatment group 1 and treatment group 2, the IOP of the ophthalmic composition solutions of Examples 1-30 were significantly lowered, among which the ophthalmic pharmaceutical compositions of Examples 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, and 30 were significantly better than those of Examples 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, however, there were no significant differences in the IOP measured values ​​and IOP change values ​​of Examples 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, and 29, and there were no significant differences in the IOP measured values ​​and IOP change values ​​of Examples 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, and 30.

[0148] Table 29. Actual measured intraocular pressure of rabbits in each group after drug administration for 10 consecutive days starting from the 10th day

[0149]

[0150]

[0151] Table 30. Differences between the measured intraocular pressure of rabbits in each group and the initial intraocular pressure (measured intraocular pressure on the 10th day) after administration for 10 consecutive days starting from the 10th day

[0152]

[0153]

[0154] Figure 2-1 and 2-2 The ophthalmic pharmaceutical composition solutions of Examples 1 to 30 and the positive control drug ( The intraocular pressure and intraocular pressure difference after administration of eye drops were measured on the 20th day. The intraocular pressure of each group of rabbits was measured once a day for 10 consecutive days. Figure 2-1 ) and the difference in intraocular pressure change ( Figure 2-2) data. Among them, the intraocular pressure change difference results show that on the 20th day: treatment group 2 compared with Example 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29 group ****: P <0.001; treatment group 2 compared with Example 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 group ****: P <0.0001; Example 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 group compared with Example 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29 group ***: P <0.001.

[0155] Example 122: Evaluation of the efficacy of the ophthalmic pharmaceutical composition solution of the present invention using the Japanese white rabbit glaucoma model

[0156] In this example, intracameral injection of compound carbomer (containing 0.3% by weight of main drug carbomer and 0.025% by weight of dexamethasone) was used to prepare a model of high intraocular pressure, and the eye drops prepared in Examples 31-60 were administered once a day to evaluate the therapeutic effect.

[0157] Experimental animals: 102 healthy male Japanese white rabbits, with an initial body weight of 2.5-3.0 kg.

[0158] Experimental groups:

[0159] Normal control group: no treatment.

[0160] Model group: The high intraocular pressure model was established without any eye drops.

[0161] Treatment group 1: The model of intraocular hypertension was established and the commercially available natadil eye drops ( Eye drops, a single-ingredient preparation containing 0.02 parts by weight of the main drug, natadil).

[0162] Treatment group 2: The model of intraocular hypertension was established and commercially available carteolol hydrochloride eye drops ( Eye drops, a single-ingredient preparation containing 2.0 parts by weight of the main drug carteolol).

[0163] Example 31 group: The viscosity enhancer is polyethylene glycol, and the pH adjuster is methanesulfonic acid. The ophthalmic pharmaceutical composition solution (containing a dual compound preparation of 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) is used.

[0164] Example 32 group: The viscosity enhancer is polyethylene glycol, and the pH adjuster is methanesulfonic acid. The ophthalmic pharmaceutical composition solution (containing a dual compound preparation of 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil)

[0165] Example 33 group: The viscosity enhancer is polyethylene glycol, and the pH adjuster is hydrobromic acid. The ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) is used.

[0166] Example 34 group: The viscosity enhancer is polyethylene glycol, and the pH adjuster is hydrobromic acid. The ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) is used.

[0167] Example 35 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is phosphoric acid.

[0168] Example 36 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is phosphoric acid.

[0169] Example 37 group: The viscosity enhancer is polyethylene glycol, and the pH adjuster is hydrochloric acid. The ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) is used.

[0170] Example 38 group: an ophthalmic pharmaceutical composition solution in which the viscosity enhancer is polyethylene glycol and the pH adjuster is hydrochloric acid (a dual compound preparation containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0171] Example 39 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is citric acid.

[0172] Example 40 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is citric acid.

[0173] Example 41 group: The viscosity enhancer is polyethylene glycol, and the pH adjuster is tartaric acid. The ophthalmic pharmaceutical composition solution (containing a dual compound preparation of 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) is used.

[0174] Example 42 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is tartaric acid.

[0175] Example 43 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is malic acid.

[0176] Example 44 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is malic acid.

[0177] Example 45 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is lactic acid.

[0178] Example 46 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is lactic acid.

[0179] Example 47 group: The viscosity enhancer is polyethylene glycol, and the pH adjuster is succinic acid. The ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) is used.

[0180] Example 48 group: The viscosity enhancer is polyethylene glycol, and the pH adjuster is succinic acid. The ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) is used.

[0181] Example 49 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is hydroiodic acid.

[0182] Example 50 group: The viscosity enhancer is polyethylene glycol, and the pH adjuster is hydroiodic acid (a dual compound preparation containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0183] Example 51 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is formic acid.

[0184] Example 52 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is formic acid.

[0185] Example 53 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is acetic acid.

[0186] Example 54 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is acetic acid.

[0187] Example 55 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is benzoic acid.

[0188] Example 56 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is benzoic acid.

[0189] Example 57 group: The viscosity enhancer is polyethylene glycol, and the pH adjuster is ethanesulfonic acid. The ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) is used.

[0190] Example 58 group: The viscosity enhancer is polyethylene glycol, and the pH adjuster is ethanesulfonic acid. The ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) is used.

[0191] Example 59 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is oxalic acid.

[0192] Example 60 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is polyethylene glycol and the pH adjuster is oxalic acid.

[0193] Model establishment: The normal control group rabbits were not treated in any way. The other 33 groups of rabbits were injected with urethane 0.8-1g / kg through the ear vein on day 0. The rabbits were anesthetized and 10μl of aqueous humor was taken out of each anterior chamber of the eye using a 1ml syringe. Then 10μl of the two-compound carbomer solution was injected. The intraocular pressure was measured every two days and the clinical manifestations were observed. In the successful model, the anterior chamber became turbid and the intraocular pressure increased significantly. After 10 days, the rabbit model of high intraocular pressure was successfully established.

[0194] Dosage regimen: According to the currently available natadil eye drops ( eye drops) and commercially available carteolol hydrochloride eye drops ( The clinical dosing regimen of eye drops) was mainly divided into the following groups: (1) Treatment group 1: commercially available natadil eye drops ( Eye drops), 50 μL per eye, once a day (9:00 PM); (2) Treatment group 2: commercially available carteolol hydrochloride eye drops ( Eye drops), 50 μL per eye, twice a day (9:00 AM, 9:00 PM); (3) Example 1-30 group: 50 μL per eye, once a day (9:00 PM). All groups were successfully established on the 10th day and began to receive medication, which lasted for 10 days. The normal control group and the model group were not given eye drops. The medication regimen is as follows Figure 1 shown.

[0195] Detection indicators and methods:

[0196] Intraocular pressure: On the 0th, 2nd, 4th, 6th, 8th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, and 20th day of the experiment, intraocular pressure was tested once a day (9:00 PM). Gently pull open the upper and lower eyelids of the rabbit, bring the tonometer close to the rabbit's eyes, adjust the distance, and gently press the measurement button. Do not touch the eyelids during the measurement process. Complete 6 measurements in sequence to obtain the single measurement value and the average value (mmHg).

[0197] Experimental results:

[0198] Intraocular pressure: At all post-dose time points during the study, the IOP values ​​of all treatment groups and example groups were significantly lower than those of the model group (Student paired t-test). At the same time, compared with treatment group 1 and treatment group 2, the IOP of the ophthalmic composition solutions of Examples 31-60 were significantly lowered, among which the ophthalmic pharmaceutical compositions of Examples 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60 were significantly better than those of Examples 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, however, there were no significant differences in the IOP measured values ​​and IOP change values ​​of Examples 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59, and there were no significant differences in the IOP measured values ​​and IOP change values ​​of Examples 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60.

[0199] Table 31. Actual measured intraocular pressure of rabbits in each group after drug administration for 10 consecutive days starting from the 10th day

[0200]

[0201]

[0202] Table 32. Changes in intraocular pressure of rabbits in each group after drug administration for 10 consecutive days starting from the 10th day

[0203]

[0204]

[0205] Figure 4-1 and 4-2 The ophthalmic pharmaceutical composition solutions of Examples 31-60 of the present invention and the positive control drug ( Eye drops) were administered once a day starting from the 10th day for 10 consecutive days. The intraocular pressure values ​​of rabbits in each group were measured on the 20th day ( Figure 4-1 ) and intraocular pressure change value ( Figure 4-2 ). Among them, the intraocular pressure change value results showed that on the 20th day: treatment group 2 was compared with Example 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59 groups ****: P < 0.0001; treatment group 2 was compared with Example 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60 groups ****: P < 0.0001; Example 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60 groups were compared with Example 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59 groups *: P < 0.05.

[0206] Example 123: Evaluation of the efficacy of the ophthalmic pharmaceutical composition solution of the present invention using the Japanese white rabbit glaucoma model

[0207] In this example, a high intraocular pressure model was prepared by intracameral injection of compound carbomer (containing 0.3% by weight of main drug carbomer and 0.025% by weight of dexamethasone), and the eye drops prepared in Examples 61-90 were administered once a day to evaluate the therapeutic effect.

[0208] Experimental animals: 102 healthy male Japanese white rabbits, with an initial body weight of 2.5-3.0 kg.

[0209] Experimental groups:

[0210] Normal control group: no treatment.

[0211] Model group: The high intraocular pressure model was established without any eye drops.

[0212] Treatment group 1: The model of intraocular hypertension was established and the commercially available natadil eye drops ( Eye drops, a single-ingredient preparation containing 0.02 parts by weight of the main drug, natadil).

[0213] Treatment group 2: The model of intraocular hypertension was established and commercially available carteolol hydrochloride eye drops ( Eye drops, a single-ingredient preparation containing 2.0 parts by weight of the main drug carteolol).

[0214] Example 61 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is methanesulfonic acid.

[0215] Example 62 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is methanesulfonic acid.

[0216] Example 63 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is hydrobromic acid.

[0217] Example 64 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is hydrobromic acid.

[0218] Example 65 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is phosphoric acid.

[0219] Example 66 group: an ophthalmic pharmaceutical composition solution in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is phosphoric acid (a dual compound preparation containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0220] Example 67 group: an ophthalmic pharmaceutical composition solution in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is hydrochloric acid (a dual compound preparation containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0221] Example 68 group: an ophthalmic pharmaceutical composition solution in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is hydrochloric acid (a dual compound preparation containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0222] Example 69 group: an ophthalmic pharmaceutical composition solution in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is citric acid (a dual compound preparation containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0223] Example 70 group: an ophthalmic pharmaceutical composition solution in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is citric acid (a dual compound preparation containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0224] Example 71 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is tartaric acid.

[0225] Example 72 group: an ophthalmic pharmaceutical composition solution in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is tartaric acid (a dual compound preparation containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0226] Example 73 group: an ophthalmic pharmaceutical composition solution in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is malic acid (a dual compound preparation containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0227] Example 74 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is malic acid.

[0228] Example 75 group: an ophthalmic pharmaceutical composition solution in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is lactic acid (a dual compound preparation containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0229] Example 76 group: an ophthalmic pharmaceutical composition solution in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is lactic acid (a dual compound preparation containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0230] Example 77 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is succinic acid.

[0231] Example 78 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is succinic acid.

[0232] Example 79 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is hydroiodic acid.

[0233] Example 80 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is hydroiodic acid.

[0234] Example 81 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is formic acid.

[0235] Example 82 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is formic acid.

[0236] Example 83 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is acetic acid.

[0237] Example 84 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is acetic acid.

[0238] Example 85 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is benzoic acid.

[0239] Example 86 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is benzoic acid.

[0240] Example 87 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is ethanesulfonic acid.

[0241] Example 88 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is ethanesulfonic acid.

[0242] Example 89 group: an ophthalmic pharmaceutical composition solution (containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is oxalic acid.

[0243] Example 90 group: an ophthalmic pharmaceutical composition solution (containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is sodium hyaluronate and the pH adjuster is oxalic acid.

[0244] Model establishment: The normal control group rabbits were not treated in any way. The other 33 groups of rabbits were injected with urethane 0.8-1g / kg through the ear vein on day 0. The rabbits were anesthetized and 10μl of aqueous humor was taken out of each anterior chamber of the eye using a 1ml syringe. Then 10μl of the two-compound carbomer solution was injected. The intraocular pressure was measured every two days and the clinical manifestations were observed. In the successful model, the anterior chamber became turbid and the intraocular pressure increased significantly. After 10 days, the rabbit model of high intraocular pressure was successfully established.

[0245] Dosage regimen: According to the currently available natadil eye drops ( eye drops) and commercially available carteolol hydrochloride eye drops ( The clinical dosing regimen of eye drops) was mainly divided into the following groups: (1) Treatment group 1: commercially available natadil eye drops ( Eye drops), 50 μL per eye, once a day (9:00 PM); (2) Treatment group 2: commercially available carteolol hydrochloride eye drops ( Eye drops), 50 μL per eye, twice a day (9:00 AM, 9:00 PM); (3) Example 1-30 group: 50 μL per eye, once a day (9:00 PM). All groups were successfully established on the 10th day and began to receive medication, which lasted for 10 days. The normal control group and the model group were not given eye drops. The medication regimen is as follows Figure 1 shown.

[0246] Detection indicators and methods:

[0247] Intraocular pressure: On the 0th, 2nd, 4th, 6th, 8th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, and 20th day of the experiment, intraocular pressure was tested once a day (9:00 PM). Gently pull open the upper and lower eyelids of the rabbit, bring the tonometer close to the rabbit's eyes, adjust the distance, and gently press the measurement button. Do not touch the eyelids during the measurement process. Complete 6 measurements in sequence to obtain the single measurement value and the average value (mmHg).

[0248] Experimental results:

[0249] Intraocular pressure: At all post-dose time points during the study, the IOP values ​​of all treatment groups and example groups were significantly lower than those of the model group (Student paired t-test). At the same time, compared with treatment group 1 and treatment group 2, the IOP of the ophthalmic composition solutions of Examples 61-90 were significantly lowered, among which the ophthalmic pharmaceutical compositions of Examples 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, and 90 were significantly better than those of Examples 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, however, there were no significant differences in the IOP measured values ​​and IOP change values ​​of Examples 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, and 89, and there were no significant differences in the IOP measured values ​​and IOP change values ​​of Examples 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, and 90.

[0250] Table 33. Actual measured intraocular pressure of rabbits in each group after drug administration for 10 consecutive days starting from the 10th day

[0251]

[0252]

[0253] Table 34. Changes in intraocular pressure of rabbits in each group after drug administration for 10 consecutive days starting from the 10th day

[0254]

[0255]

[0256] Figure 6-1 and 6-2 The ophthalmic pharmaceutical composition solutions of Examples 61-90 of the present invention and the positive control drug ( Eye drops) were administered once a day starting from the 10th day for 10 consecutive days. The intraocular pressure changes of rabbits in each group were measured on the 20th day ( Figure 6-1 ) and measured intraocular pressure ( Figure 6-2) bar graph. The results of intraocular pressure change values ​​showed that on the 20th day: treatment group 2 was compared with Example 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89 group ***: P < 0.001; treatment group 2 was compared with Example 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90 group ****: P < 0.0001; Example 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90 group was compared with Example 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89 group *: P < 0.05.

[0257] Example 124: Evaluation of the efficacy of the ophthalmic pharmaceutical composition solution of the present invention using the Japanese white rabbit glaucoma model

[0258] In this example, a high intraocular pressure model was prepared by intracameral injection of compound carbomer (containing 0.3% by weight of main drug carbomer and 0.025% by weight of dexamethasone), and the eye drops prepared in Examples 91-120 were administered once a day to evaluate the therapeutic effect.

[0259] Experimental animals: 102 healthy male Japanese white rabbits, with an initial body weight of 2.5-3.0 kg.

[0260] Experimental groups:

[0261] Normal control group: no treatment.

[0262] Model group: The high intraocular pressure model was established without any eye drops.

[0263] Treatment group 1: The model of intraocular hypertension was established and the commercially available natadil eye drops ( Eye drops, a single-ingredient preparation containing 0.02 parts by weight of the main drug, natadil).

[0264] Treatment group 2: The model of intraocular hypertension was established and commercially available carteolol hydrochloride eye drops ( Eye drops, a single-ingredient preparation containing 2.0 parts by weight of the main drug carteolol).

[0265] Example 91 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with methanesulfonic acid as the pH adjuster (containing a dual compound preparation of 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0266] Example 92 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with methanesulfonic acid as the pH adjuster (containing a dual compound preparation of 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0267] Example 93 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with hydrobromic acid as the pH adjuster (a dual compound preparation containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0268] Example 94 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with hydrobromic acid as the pH adjuster (a dual compound preparation containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0269] Example 95 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with phosphoric acid as the pH adjuster (containing a dual compound preparation of 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0270] Example 96 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with phosphoric acid as the pH adjuster (containing a dual compound preparation of 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0271] Example 97 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with hydrochloric acid as the pH adjuster (a dual compound preparation containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0272] Example 98 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with hydrochloric acid as the pH adjuster (a dual compound preparation containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0273] Example 99 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with citric acid as the pH adjuster (containing a dual compound preparation of 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0274] Example 100 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with citric acid as the pH adjuster (containing a dual compound preparation of 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0275] Example 101 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with tartaric acid as the pH adjuster (containing a dual compound preparation of 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0276] Example 102 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with tartaric acid as the pH adjuster (containing a dual compound preparation of 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0277] Example 103 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with malic acid as the pH adjuster (a dual compound preparation containing 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0278] Example 104 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with malic acid as the pH adjuster (a dual compound preparation containing 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0279] Example 105 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with lactic acid as the pH adjuster (containing a dual compound preparation of 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0280] Example 106 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with lactic acid as the pH adjuster (containing a dual compound preparation of 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0281] Example 107 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with succinic acid as the pH adjuster (containing a dual compound preparation of 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0282] Example 108 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with succinic acid as the pH adjuster (containing a dual compound preparation of 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0283] Example 109 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with hydroiodic acid as the pH adjuster (containing a dual compound preparation of 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0284] Example 110 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with hydroiodic acid as the pH adjuster (containing a dual compound preparation of 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0285] Example 111 Group: An ophthalmic pharmaceutical composition solution without a viscosity enhancer and with formic acid as the pH adjuster (containing a dual compound preparation of 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0286] Example 112 Group: An ophthalmic pharmaceutical composition solution without a viscosity enhancer and with formic acid as the pH adjuster (containing a dual compound preparation of 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0287] Example 113 Group: An ophthalmic pharmaceutical composition solution without a viscosity enhancer and with acetic acid as the pH adjuster (containing a dual compound preparation of 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0288] Example 114 Group: An ophthalmic pharmaceutical composition solution without a viscosity enhancer and with acetic acid as the pH adjuster (containing a dual compound preparation of 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0289] Example 115 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with benzoic acid as the pH adjuster (containing a dual compound preparation of 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0290] Example 116 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with benzoic acid as the pH adjuster (containing a dual compound preparation of 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0291] Example 117 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with ethanesulfonic acid as the pH adjuster (containing a dual compound preparation of 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0292] Example 118 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with ethanesulfonic acid as the pH adjuster (containing a dual compound preparation of 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0293] Example 119 Group: An ophthalmic pharmaceutical composition solution without a viscosity enhancer and with oxalic acid as the pH adjuster (containing a dual compound preparation of 1.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0294] Example 120 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with oxalic acid as the pH adjuster (containing a dual compound preparation of 2.0 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil).

[0295] Model establishment: The normal control group rabbits were not treated in any way. The other 33 groups of rabbits were injected with urethane 0.8-1g / kg through the ear vein on day 0. The rabbits were anesthetized and 10μl of aqueous humor was taken out of each anterior chamber of the eye using a 1ml syringe. Then 10μl of the two-compound carbomer solution was injected. The intraocular pressure was measured every two days and the clinical manifestations were observed. In the successful model, the anterior chamber became turbid and the intraocular pressure increased significantly. After 10 days, the rabbit model of high intraocular pressure was successfully established.

[0296] Dosage regimen: According to the currently available natadil eye drops ( eye drops) and commercially available carteolol hydrochloride eye drops ( The clinical dosing regimen of eye drops) was mainly divided into the following groups: (1) Treatment group 1: commercially available natadil eye drops ( Eye drops), 50 μL per eye, once a day (9:00 PM); (2) Treatment group 2: commercially available carteolol hydrochloride eye drops ( Eye drops), 50 μL per eye, twice a day (9:00 AM, 9:00 PM); (3) Example 1-30 group: 50 μL per eye, once a day (9:00 PM). All groups were successfully established on the 10th day and began to receive medication, which lasted for 10 days. The normal control group and the model group were not given eye drops. The medication regimen is as follows Figure 1 shown.

[0297] Detection indicators and methods:

[0298] Intraocular pressure: On the 0th, 2nd, 4th, 6th, 8th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, and 20th day of the experiment, intraocular pressure was tested once a day (9:00 PM). Gently pull open the upper and lower eyelids of the rabbit, bring the tonometer close to the rabbit's eyes, adjust the distance, and gently press the measurement button. Do not touch the eyelids during the measurement process. Complete 6 measurements in sequence to obtain the single measurement value and the average value (mmHg).

[0299] Experimental results:

[0300] Intraocular pressure: At all post-dose time points during the study, the IOP values ​​of all treatment groups and example groups were significantly lower than those of the model group (Student paired t-test). At the same time, compared with treatment group 1 and treatment group 2, the IOP of the ophthalmic composition solutions of Examples 91-120 were significantly lowered, among which the ophthalmic pharmaceutical compositions of Examples 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, and 120 were significantly better than those of Examples 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 116, 117, 118, 119, 120. 17, 119 groups of ophthalmic pharmaceutical compositions; however, there were no significant differences in the IOP measured values ​​and IOP change values ​​of Examples 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, and 119 groups, and there were no significant differences in the IOP measured values ​​and IOP change values ​​of Examples 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, and 120 groups.

[0301] Table 35: The measured intraocular pressure of rabbits in each group after drug administration for 10 consecutive days starting from the 10th day

[0302]

[0303]

[0304] Table 36: Changes in intraocular pressure of rabbits in each group after drug administration for 10 consecutive days starting from the 10th day

[0305]

[0306]

[0307] Figure 8-1 and 8-2 The ophthalmic pharmaceutical composition solutions of Examples 91-120 and the positive control drug ( Eye drops) were administered once a day starting from the 10th day for 10 consecutive days. The intraocular pressure changes of rabbits in each group were measured on the 20th day ( Figure 8-1 ) and measured intraocular pressure ( Figure 8-2 ) data. The results of intraocular pressure change values ​​show that on the 20th day: Treatment Group 2 was compared with Examples 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, and 119 *: P < 0.05; Treatment Group 2 was compared with Examples 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, Compared with groups 118 and 120, **: P < 0.01; compared with groups 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120 and groups 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, *: P < 0.05.

[0308] Figure 9-1 and 9-2 The results show that there is a significant difference in the intraocular pressure change value of the ophthalmic pharmaceutical composition solution on the 20th day between the group without viscosity increasing agent and the group with hydroxypropyl methylcellulose (HPMC), wherein Figure 9-1 represents an ophthalmic pharmaceutical composition solution containing 1% carteolol, Figure 9-2 The results showed that the 1% carteolol HPMC group was compared with the group without viscosity enhancer **: P < 0.01; the 2% carteolol HPMC group was compared with the group without viscosity enhancer **: P < 0.01.

[0309] Figure 10-1 and 10-2The graph shows the significant difference in the intraocular pressure change values ​​of the ophthalmic pharmaceutical composition solution on the 20th day between the group without viscosity enhancer and the group with polyethylene glycol (PEG), wherein Figure 10-1 represents an ophthalmic pharmaceutical composition solution containing 1% carteolol, Figure 10-2 The results showed that the 1% carteolol PEG group was compared with the group without viscosity enhancer ***: P < 0.001; the 2% carteolol PEG group was compared with the group without viscosity enhancer **: P < 0.01.

[0310] Figure 11-1 and 11-2 : is a graph showing the significant difference in the intraocular pressure change values ​​of the ophthalmic pharmaceutical composition solution on the 20th day between the group without viscosity enhancer and the group with sodium hyaluronate (HA), wherein Figure 11-1 represents an ophthalmic pharmaceutical composition solution containing 1% carteolol, Figure 11-2 It represents an ophthalmic pharmaceutical composition solution with a dosage of 2% carteolol. The results show that the 1% carteolol HA group is compared with the group without viscosity enhancer **: P < 0.01; the 2% carteolol HA group is compared with the group without viscosity enhancer *: P < 0.05. All documents mentioned in the present invention are cited as references in this application, just as each document is cited as a reference separately.

[0311] Examples 126-129: Dual compound eye drops prepared with hydroxypropyl methylcellulose as a viscosity enhancer and different pH adjusters

[0312] Table 37. Preparation and formulation of topical ophthalmic pharmaceutical composition solution for reducing intraocular pressure are as follows:

[0313] Example Natadil Timolol Boric acid Mannitol Hydroxypropyl methylcellulose Methanesulfonic acid Maleic acid Add water for injection to 126 20mg 250mg 50mg 5000mg 500mg Q / 100mL 127 20mg 500mg 50mg 5000mg 500mg Q / 100mL 128 20mg 250mg 50mg 5000mg 500mg / Q 100mL 129 20mg 500mg 50mg 5000mg 500mg / Q 100mL

[0314] The preparation process is as follows: (1) weighing 90% of the prescribed amount of water for injection, adding the prescribed amount of timolol, boric acid, mannitol, natridil and hypromellose, adding different pH adjusters, stirring and adjusting the pH to 4.5-5.4; (2) adding water for injection to the full amount of the prescription, stirring evenly and making the volume reach 100%; (3) putting the solution of step 2 into a low-density polyethylene medicinal eye drop bottle, and studying its stability under different storage temperature conditions.

[0315] Table 38. Content of each main drug component in Examples 126-129 when stored at 5°C for 24 months

[0316] Example Natadil Timolol 126 99.2 100.3 127 98.7 99.2 128 100.3 98.7 129 99.2 99.1

[0317] Table 39. Commercially available eye drops stored at 5°C for 24 months ( The content of each main drug component in eye drops

[0318]

[0319] According to Examples 126-129, the formulations containing natridil and timolol have good stability under storage conditions of 5° C. for 24 months, meeting the requirements for commercially available eye drops ( Eye drops) Storage conditions requirements before opening.

[0320] Table 4. Content of each main drug component in Examples 126-129 when stored at 25°C for 6 weeks

[0321] Example Natadil Timolol 126 99.4 99.5 127 99.9 100.1 128 99.1 99.6 129 99.9 99.2

[0322] Table 40. Commercially available eye drops stored at 25°C for 6 weeks ( The content of each main drug component in eye drops

[0323]

[0324] According to Examples 126-129, the preparations containing natridil and timolol have good stability under storage conditions of 25° C. for 6 weeks, meeting the requirements for commercially available eye drops ( Eye drops) Storage conditions requirements after opening.

[0325] Table 41. Content of each main drug component in Examples 126-129 when stored at 40°C for 14 days

[0326] Example Natadil Timolol 126 99.3 99.1 127 100.2 99.9 128 99.6 99.3 129 99.1 88.1

[0327] Table 42. Commercial eye drops stored at 40°C for 14 days ( Eye drops) Content of each main drug component

[0328]

[0329] According to Examples 126-129, the preparations containing natridil and timolol have good stability for 14 days under storage conditions of 40°C, meeting the requirements for commercially available eye drops ( Eye drops) short-term deviation from storage conditions requirements.

[0330] Examples 130-133: Thickener-free dual compound eye drops prepared with different pH adjusters

[0331] Table 43. Preparation and formulation of topical ophthalmic pharmaceutical composition solution for reducing intraocular pressure are as follows:

[0332]

[0333] The preparation process is as follows: (1) weighing 90% of the prescribed amount of water for injection, adding the prescribed amount of timolol, boric acid, mannitol, and natridil, adding different pH adjusters, stirring, and adjusting the pH to 4.5-5.4; (2) adding water for injection to the full amount of the prescription, stirring evenly and making the volume reach 100%; (3) putting the solution of step 2 into a low-density polyethylene medicinal eye drop bottle, and after testing, the stability of the composition under different storage temperature conditions is good.

[0334] Example 134: Evaluation of the efficacy of the ophthalmic pharmaceutical composition solution of the present invention using the Japanese white rabbit glaucoma model

[0335] In this example, a high intraocular pressure model was prepared by intracameral injection of compound carbomer (containing 0.3% by weight of main drug carbomer and 0.025% by weight of dexamethasone), and the eye drops prepared in Examples 126-129 were administered once a day to evaluate the therapeutic effect.

[0336] Experimental animals: 102 healthy male Japanese white rabbits, with an initial body weight of 2.5-3.0 kg.

[0337] Experimental groups:

[0338] Normal control group: no treatment.

[0339] Model group: The high intraocular pressure model was established without any eye drops.

[0340] Treatment group 1: The model of intraocular hypertension was established and the commercially available natadil eye drops ( Eye drops, a single-ingredient preparation containing 0.02 parts by weight of the main drug, natadil).

[0341] Treatment group 3: The model of intraocular hypertension was established and commercially available timolol maleate eye drops ( Eye drops, a single-ingredient preparation containing 0.5 parts by weight of the main drug timolol).

[0342] Example 126 group: an ophthalmic pharmaceutical composition solution (containing 0.25 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is methanesulfonic acid.

[0343] Example 127 group: an ophthalmic pharmaceutical composition solution (containing 0.5 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is methanesulfonic acid.

[0344] Example 128 group: an ophthalmic pharmaceutical composition solution (containing 0.25 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is maleic acid.

[0345] Example 129 group: an ophthalmic pharmaceutical composition solution (containing 0.5 parts by weight of the main drug carteolol and 0.02 parts by weight of natadil) in which the viscosity enhancer is hypromellose and the pH adjuster is maleic acid.

[0346] Model establishment: The normal control group rabbits were not treated in any way. On day 0, the other 7 groups of rabbits were injected with urethane 0.8-1g / kg through the ear vein. Under general anesthesia, 10μl of aqueous humor was taken out of each anterior chamber of the eye using a 1ml syringe, and then 10μl of the two-combination compound carbomer solution was injected. The intraocular pressure was measured every two days and the clinical manifestations were observed. In the successful model, the anterior chamber became turbid and the intraocular pressure increased significantly. After 10 days, the rabbit model of high intraocular pressure was successfully established.

[0347] Dosage regimen: According to the currently available natadil eye drops ( eye drops) and commercially available timolol maleate eye drops ( The clinical dosing regimen of eye drops) was mainly divided into the following groups: (1) Treatment group 1: commercially available natadil eye drops ( Eye drops), 50 μL per eye, once a day (9:00 PM); (2) Treatment group 3: commercially available timolol maleate eye drops ( Eye drops), 50 μL per eye, twice a day (9:00 AM, 9:00 PM); (3) Example 126-129 group: 50 μL per eye, once a day (9:00 PM). All groups were successfully established on the 10th day and began to receive medication, which lasted for 10 days. The normal control group and the model group were not given eye drops. The medication regimen is as follows Figure 1 shown.

[0348] Detection indicators and methods:

[0349] Intraocular pressure: On the 0th, 2nd, 4th, 6th, 8th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, and 20th day of the experiment, intraocular pressure was tested once a day (9:00 PM). Gently pull open the upper and lower eyelids of the rabbit, bring the tonometer close to the rabbit's eyes, adjust the distance, and gently press the measurement button. Do not touch the eyelids during the measurement process. Complete 6 measurements in sequence to obtain the single measurement value and the average value (mmHg).

[0350] Experimental results:

[0351] Intraocular pressure: At all post-dose time points during the study, the IOP values ​​of all treatment groups and example groups were significantly reduced compared with the model group (Student paired t-test). At the same time, compared with treatment group 1 and treatment group 3, the IOP of the ophthalmic composition solutions of Example 126-129 groups was significantly reduced, among which the ophthalmic pharmaceutical compositions of Example 127 and 129 groups were significantly better than those of Example 126 and 128 groups; however, there was no significant difference in the IOP measured values ​​and IOP change values ​​of Example 126 and 128 groups, and there was no significant difference in the IOP measured values ​​and IOP change values ​​of Example 127 and 129 groups.

[0352] Table 44. Actual measured intraocular pressure of rabbits in each group after drug administration for 10 consecutive days starting from the 10th day

[0353]

[0354] Table 45. Starting from the 10th day, the intraocular pressure of each group of rabbits was measured for 10 consecutive days and the difference between the initial intraocular pressure (the intraocular pressure measured on the 10th day)

[0355]

[0356]

[0357] Fig.12 The ophthalmic pharmaceutical composition solutions of Examples 126-129 and the positive control drug ( The intraocular pressure and intraocular pressure difference after administration of eye drops were measured on the 20th day. The intraocular pressure of each group of rabbits was measured once a day for 10 consecutive days. Figure 2-1 ) and the difference in intraocular pressure change ( Figure 2-2 ). The difference in intraocular pressure changes showed that on the 20th day: treatment group 3 compared with Example 126 and 128 groups ***: P < 0.001; treatment group 3 compared with Example 127 and 129 groups ****: P < 0.0001; Example 127 and 129 groups compared with Example 126 and 128 groups ***: P < 0.001.

[0358] Example 135: Evaluation of the efficacy of the ophthalmic pharmaceutical composition solution of the present invention using the Japanese white rabbit glaucoma model

[0359] In this example, a high intraocular pressure model was prepared by intracameral injection of compound carbomer (containing 0.3% by weight of main drug carbomer and 0.025% by weight of dexamethasone), and the eye drops prepared in Examples 130-133 were administered once a day to evaluate the therapeutic effect.

[0360] Experimental animals: 102 healthy male Japanese white rabbits, with an initial body weight of 2.5-3.0 kg.

[0361] Experimental groups:

[0362] Normal control group: no treatment.

[0363] Model group: The high intraocular pressure model was established without any eye drops.

[0364] Treatment group 1: The model of intraocular hypertension was established and the commercially available natadil eye drops ( Eye drops, a single-ingredient preparation containing 0.02 parts by weight of the main drug, natadil).

[0365] Treatment group 3: The model of intraocular hypertension was established and commercially available timolol maleate eye drops ( Eye drops, a single-ingredient preparation containing 0.5 parts by weight of the main drug carteolol).

[0366] Example 130 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with methanesulfonic acid as the pH adjuster (containing a dual compound preparation of 0.25 parts by weight of the main drug timolol and 0.02 parts by weight of natadil).

[0367] Example 131 Group: An ophthalmic pharmaceutical composition solution without a viscosity enhancer and with methanesulfonic acid as the pH adjuster (containing a dual compound preparation of 0.5 parts by weight of the main drug timolol and 0.02 parts by weight of natadil).

[0368] Example 132 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with maleic acid as the pH adjuster (containing a dual compound preparation of 0.25 parts by weight of the main drug timolol and 0.02 parts by weight of natadil).

[0369] Example 133 group: an ophthalmic pharmaceutical composition solution without a viscosity enhancer and with maleic acid as the pH adjuster (containing a dual compound preparation of 0.5 parts by weight of the main drug timolol and 0.02 parts by weight of natadil).

[0370] Model establishment: The normal control group rabbits were not treated in any way. On day 0, the other 7 groups of rabbits were injected with urethane 0.8-1g / kg through the ear vein. Under general anesthesia, 10μl of aqueous humor was taken out of each anterior chamber of the eye using a 1ml syringe, and then 10μl of the two-combination compound carbomer solution was injected. The intraocular pressure was measured every two days and the clinical manifestations were observed. In the successful model, the anterior chamber became turbid and the intraocular pressure increased significantly. After 10 days, the rabbit model of high intraocular pressure was successfully established.

[0371] Dosage regimen: According to the currently available natadil eye drops ( eye drops) and commercially available timolol maleate eye drops ( The clinical dosing regimen of eye drops) was mainly divided into the following groups: (1) Treatment group 1: commercially available natadil eye drops ( Eye drops), 50 μL per eye, once a day (9:00 PM); (2) Treatment group 3: commercially available timolol maleate eye drops ( Eye drops), 50 μL per eye, twice a day (9:00 AM, 9:00 PM); (3) Example 1-30 group: 50 μL per eye, once a day (9:00 PM). All groups were successfully established on the 10th day and began to receive medication, which lasted for 10 days. The normal control group and the model group were not given eye drops. The medication regimen is as follows Figure 1 shown.

[0372] Detection indicators and methods:

[0373] Intraocular pressure: On the 0th, 2nd, 4th, 6th, 8th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, and 20th day of the experiment, intraocular pressure was tested once a day (9:00 PM). Gently pull open the upper and lower eyelids of the rabbit, bring the tonometer close to the rabbit's eyes, adjust the distance, and gently press the measurement button. Do not touch the eyelids during the measurement process. Complete 6 measurements in sequence to obtain the single measurement value and the average value (mmHg).

[0374] Experimental results:

[0375] Intraocular pressure: At all post-dose time points during the study, the IOP values ​​of all treatment groups and example groups were significantly reduced compared to the model group (Student paired t-test). At the same time, compared with treatment group 1 and treatment group 3, the IOP of the ophthalmic composition solutions of Example 130-133 groups were significantly reduced, among which the ophthalmic pharmaceutical composition of Example 131 and 133 groups had significantly better intraocular pressure-lowering effects than the ophthalmic pharmaceutical composition of Example 130 and 132 groups; however, there was no significant difference in the IOP measured values ​​and IOP change values ​​of Example 130 and 132 groups, and there was no significant difference in the IOP measured values ​​and IOP change values ​​of Example 131 and 13 groups.

[0376] Table 46: The measured intraocular pressure of rabbits in each group after drug administration for 10 consecutive days starting from the 10th day

[0377]

[0378] Table 47: Changes in intraocular pressure of rabbits in each group after drug administration for 10 consecutive days starting from the 10th day

[0379]

[0380] Figure 13-1 and 13-2The ophthalmic pharmaceutical composition solutions of Examples 126-129 of the ophthalmic pharmaceutical composition solution group of the present invention with hydroxypropyl methylcellulose (HPMC) and the positive control drug ( Eye drops) were administered once a day starting from the 10th day for 10 consecutive days. The intraocular pressure changes of rabbits in each group were measured on the 20th day ( Figure 13-1 ) and measured intraocular pressure ( Figure 13-2 ) data. The intraocular pressure change results showed that on the 20th day: treatment group 3 compared with Example 126 and 128 groups ***: P < 0.001; treatment group 3 compared with Example 127 and 129 groups ***: P < 0.001; Example 126 compared with Example 127 group *: P < 0.05; Example 128 compared with Example 129 group *: P < 0.05.

[0381] Figure 14-1 and 14-2 The results show that there is a significant difference in the intraocular pressure change value of the ophthalmic pharmaceutical composition solution on the 20th day between the group without viscosity increasing agent and the group with hydroxypropyl methylcellulose (HPMC), wherein Figure 14-1 It means an ophthalmic pharmaceutical composition solution containing 0.25% timolol. Figure 14-2 It represents an ophthalmic pharmaceutical composition solution with a dosage of 0.5% timolol. The results show that the 0.25% timolol HPMC group is compared with the group without viscosity enhancer***: P<0.001; the 0.5% timolol HPMC group is compared with the group without viscosity enhancer***: P<0.001. All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually.

Claims

1. A dual compound pharmaceutical composition for treating glaucoma, characterized in that: The pharmaceutical composition comprises: carteolol or timolol, natridil, a buffer, a tonicity agent, a pH regulator, a viscosity enhancer and water for injection.

2. The dual compound pharmaceutical composition according to claim 1, characterized in that: The ophthalmic pharmaceutical composition comprises (1) 0.02% w / v to 4.0% w / v of carteolol free base or timolol free base; (2) 0.005% w / v to 0.1% w / v of natriuretic acid free base; (3) 0.01% w / v to 10.0% w / v tonicity agent; (4) 0.01% w / v to 1.0% w / v buffer; (5) 0.1% w / v to 1.0% w / v of a viscosity increasing agent; v is the volume of the composition system after the injection water is added; (6) adjusting the pH to 4.5 to 5.4 using a pH adjuster; (7) Osmolality is 280 to 320 mOsmol / kg.

3. The dual compound pharmaceutical composition according to claim 2, characterized in that: The ophthalmic pharmaceutical composition comprises (1) 0.02% w / v to 2.0% w / v of carteolol free base or timolol free base; (2) 0.005% w / v to 0.02% w / v of natadil free base; (3) 0.01% w / v to 10.0% w / v tonicity agent; (4) 0.01% w / v to 1.0% w / v buffer; (5) 0.1% w / v to 1.0% w / v of a viscosity increasing agent; v is the volume of the composition system after the injection water is added; (6) adjusting the pH to 4.5 to 5.4 using a pH adjuster; (7) Osmolality is 280 to 320 mOsmol / kg.

4. The dual compound pharmaceutical composition according to claim 1, characterized in that: The buffer is selected from boric acid and borates, sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate monohydrate, sodium phosphate anhydrate, citric acid or its salts, carbonic acid, gluconic acid or its salts, acetic acid or its salts, phosphoric acid or its salts, or any combination thereof.

5. The dual compound pharmaceutical composition according to claim 1, characterized in that: The borate is borax.

6. The dual compound pharmaceutical composition according to claim 1, characterized in that: The tonicity agent is selected from glycerin, sorbitol, mannitol, propylene glycol, erythritol, arabitol, xylitol, ribitol, galactitol, polyethylene glycol, lactitol, mannitol, dextrose, sodium chloride, potassium chloride and calcium chloride, or any combination thereof.

7. The dual compound pharmaceutical composition according to claim 1, characterized in that: The pH regulator is selected from one or more of methanesulfonic acid, hydrobromic acid, phosphoric acid, hydrochloric acid, citric acid, tartaric acid, malic acid, lactic acid, succinic acid, hydroiodic acid, formic acid, acetic acid, benzoic acid, ethanesulfonic acid, oxalic acid, sodium hydroxide, and tromethamine.

8. The dual compound pharmaceutical composition according to claim 1, characterized in that: The viscosity enhancer is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium hydroxyethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, polyethylene glycol, sodium hyaluronate, sodium alginate hyaluronic acid, chitosan, and polyvinyl pyrrolidone.

9. Use of the dual compound pharmaceutical composition according to any one of claims 1 to 8 in the preparation of a medicament for preventing or treating eye diseases.

10. The use according to claim 9, characterized in that The eye disease is glaucoma, ocular hypertension and / or symptoms associated therewith.

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